Cocaine addiction is established and maintained by several interrelated factors. The strong positive reinforcing properties of cocaine are clearly necessary for both its initial use and its repetitive self- administration. With prolonged use, other factors play a role in maintaining cocaine dependence including long-lasting neuroadaptations. As such, it is critical for the design of therapeutics to treat cocaine addiction to identify the mechanisms underlying cocaine-induced reward and plasticity. One molecule that recently has received attention for its role in psychiatric disorders and the therapeutics used to treat them, as well as in synaptic plasticity, is glycogen synthase kinase-3 (GSK3). Evidence suggests that GSK3 is uniquely situated to modulate neuronal function and plasticity. Our published and preliminary data demonstrate that GSK3 activity is necessary for cocaine-induced behaviors including reward, hyperlocomotion, and behavioral sensitization, and that the activity of GSK3 is regulated during cocaine exposure in a brain-region specific manner. Our data also demonstrate that agents that inhibit GSK3 are effective at blocking not only cocaine-induced reward, but also the reconsolidation of cocaine contextual memories, thus attenuating cocaine-seeking behaviors. The following specific aims are proposed to address the central hypothesis that GSK3 is a critical molecular mediator of cocaine-induced actions including drug reward and drug-seeking behaviors. In Specific Aim 1, the contribution of GSK3 to the rewarding effects of cocaine will be established using the place preference procedure. The role of GSK3 in reconsolidation of cocaine contextual memories and reinstatement to cocaine-seeking behavior will be determined. In Specific Aim 2, changes in GSK3 activity will be measured following acute and repeated cocaine administration and following expression of cocaine conditioned place preference. The receptor systems activated by cocaine that engage GSK3 signaling will be elucidated. Regulation of the upstream kinase, Akt, will also be measured. Immunohistochemical analyses are proposed in Aim 3 to determine the specific neuronal pathways where regulation of GSK3 occurs. Specific Aim 4 will elucidate sites of action of GSK3 inhibitors in modulating cocaine reward and reconsolidation. Taken together, these results will provide critical information about the molecular mechanisms driving cocaine addiction-related behaviors and have the potential of establishing GSK3 as a novel target for therapeutics to treat cocaine dependence. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine the role of the GSK3 signaling pathway in the actions of cocaine as related to addiction. These studies will determine if modulation of GSK3 can interfere with processes involved in cocaine addictive behaviors and how exposure to cocaine alters this important intracellular pathway in brain regions critically involved in mediating the rewarding and conditioned stimulus effects of drugs of abuse. These studies aim to provide preclinical data to establish GSK3 as a novel target for the treatment of cocaine addiction which could be a major public health advancement and significantly reduce the costs of addiction to society.